Influence of Sugar Amine Regiochemistry on Digitoxigenin

Letter pubs.acs.org/acsmedchemlett

Influence of Sugar Amine Regiochemistry on Digitoxigenin Neoglycoside Anticancer Activity Jianjun Zhang,†,‡ Larissa V. Ponomareva,†,‡ Nitin S. Nandurkar,†,‡ Yaxia Yuan,‡ Lei Fang,‡ Chang-Guo Zhan,‡ and Jon S. Thorson*,†,‡ †

Center for Pharmaceutical Research and Innovation and ‡Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536-0596, United States

Downloaded by EMORY UNIV on August 25, 2015 | http://pubs.acs.org Publication Date (Web): August 18, 2015 | doi: 10.1021/acsmedchemlett.5b00120

S Supporting Information *

ABSTRACT: The synthesis of a set of digitoxigenin neogluco/ xylosides and corresponding study of their anticancer SAR revealed sugar amine regiochemistry has a dramatic effect upon activity. Specifically, this study noted sugar 3-amino followed by 4-amino-substitution to be most advantageous where the solvent accessibility of the appended amine within neoglycosideNa+,K+-ATPase docked models correlated with increased anticancer potency. This study presents a preliminary model for potential further warhead optimization in the context of antibody-directed steroidal glycosides and extends the demonstrated compatibility of aminosugars in the context of neoglycosylation. KEYWORDS: Regiochemistry, sugar, digitoxigenin, neoglycosylation

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teroidal glycosides (exemplified by digitoxin and digoxin, Figure 1) are a family of natural products that inhibit the Na+,K+-ATPase (NKA) catalytic alpha subunit, the corresponding positive inotropic effect of which serves as the basis for their use in treating congestive heart failure.1−4 Consistent with retrospective studies that revealed a reduced recurrence rate of breast cancer among patients on digitalis,5−9 up-regulation of NKA has been observed in many cancers including NSCLC, ovarian, pancreatic, colorectal, glioblastoma, and melanoma.2−4 Recent research has revealed up to half of the NKA within cancer cells to reside within caveolae (“lipid rafts”) and to mediate cell signaling processes via the oncogenic protein Src.10−19 Inhibition of NKA within this context initiates kinase-dependent events involving EGFR, MAPK, PKC, or TGF-beta signaling pathways that induce cell apoptosis.12−14,16,17 Naturally occurring and semisynthetic steroidal glycosides display notable in vitro anticancer potency (including prostate,20,21 lung,22−26 breast,27 colorectal,28 leukemia, and myeloma29), efficacy in mouse models,30 and importantly, more recently noted as triggering immunogenic cell death.31 Yet, while specific analogues that display reduced ionotropic and increased cancer cell cytoxicity activity have been reported,32 the narrow therapeutic index (by virtue of cardiotoxicity and neurotoxicity) has hampered steroidal glycoside clinical development for the treatment of cancer.30,33−35 Steroidal aminoglycosides are attractive in this regard as the presence of an aminosugar reduces blood−brain barrier penetration and thereby offers potential for reduced neurotoxicity.36−39 In addition, specific aminosugarbearing analogues of digitoxigenin and proscillaridin have been employed in the context of cancer-targeting antibodies where the appended amino group also presents a convenient handle for antibody conjugation.40,41 While some reported mono-42−44 or © XXXX American Chemical Society

Figure 1. Representative naturally occurring cardenolides and bufadienolies with demonstrated anticancer activity (conjugated sugars highlighted in blue).

oligosaccharide-based45−48 structure−activity relationship (SAR) exists, there is a lack of fundamental anticancer SAR with respect to the sugar amine regiochemistry. Herein we describe a model Received: March 20, 2015 Accepted: August 12, 2015

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DOI: 10.1021/acsmedchemlett.5b00120 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters


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Figure 2. Overall synthetic strategy and corresponding steroidal neoglycoside products (sugar amino/azido functionalization highlighted in blue). (A) General synthetic scheme for neoaglycon (1α and 1β) synthesis and utilization beginning from digitoxin. (B) Digitoxigenin 3S-neoglycosides from aglycon 1β. (C) Digitoxigenin 3R-neoglycosides from aglycon 1α.

neoglycosylation of both 1α and 1β with a set of azidosugars (2-azido-2-deoxy-D-glucose, 3-azido-3-deoxy-D-glucose, 4-azido4-deoxy-D-glucose, 6-azido-6-deoxy-D-glucose, 2-azido-2-deoxyD-xylose, 3-azido-3-deoxy-D-xylose, and 4-azido-4-deoxy-Dxylose) followed by reduction.53 Comparator controls deriving from neoglycosylation of 1α and 1β with D-glucose were also generated to ultimately provide a cumulative set of 22 digitoxigenin neoglycosides for bioactivity assays (Figure 2B,C). The yield of neoglycosylation varied by the nature of the sugar employed with an average isolated yield of 40%. Neoglycoside product characterization revealed all the members to adopt 1,2-transanomer exclusively. The set of 22 pure digitoxigenin neoglycosides and two parental aglycons were assessed in vitro against non-small cell lung cancer cell line A549 (Figure 3). Consistent with the prior single comparison of a 3S- and 3R-neoglucoside,32 all 3S-digitoxigenin

study on the impact of sugar amino substitution upon the anticancer activity of a series of digitoxigenin aminoxylosides and aminoglucosides. Consistent with computed NKA-ligand docked models, this study reveals digitoxigenin neoglycosylation with 3-aminosugars followed closely by 4-aminosugars as most advantageous where the determined potency parallels the predicted solvent accessibility of the sugar amine. Importantly, this study presents a preliminary model for potential further warhead optimization in the context of antibody-directed steroidal glycosides. In addition, this study also extends the demonstrated compatibility of aminosugars in the context of neoglycosylation.49−52 Preparation of digitoxigenin neoaglycon (Figure 2A) was accomplished as previously described from digitoxin to furnish 0.75 g of 1β (24% yield) and 0.96 g of 1α (30% yield).32 The synthesis of aminosugar-containing neoglycosides was accomplished via a simple two step process beginning with B




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Figure 3. Anticancer activity of the most active digitoxigenin neoglycosides and comparator controls against the A549 (human lung adenocarcinoma) cancer cell line. Reciprocal IC50 values and the structures of the corresponding sugars conjugated for each 1α/1β pairing are displayed. As a reference, the most active analogue in this series (Dg18) displayed an IC50 of 10 ± 1 nM, while the least active analogue represented (Dg12) displayed an IC50 of 1600 ± 400 nM. Three independent viability assays were conducted in triplicate of dose−response experiments over nine concentrations at 3-fold dilutions. IC50 values (and mean ± standard errors) can be found in the Supporting Information.

Figure 4. Human NKA-cardenolide neoglycoside docked models (cardenolide neoglycoside, orange ball and stick; NKA α1, β1, and γ subunits in cyan, green, and purple, respectively). Hydrogen bonds are illustrated as dotted lines with key distances in Å. (A) The overall NKA complex: (B) Dg17; (C) Dg18; (D) Dg08; (E) Dg10; (F) Dg16. (G) Predicted binding mode of a (3S)-2′-amino-2′-deoxy-D-glucoside (analogue not synthesized) predicts a potential rotation of sugar to afford the putative favorable electrostatic interaction between the glycosyl C2′-amine and NKA D891 side chain carboxylate. C




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chemoselective functionality for conjugation to cancer-targeting antibodies as a strategy to improve their therapeutic index and enable their use in the treatment of cancer.

neoglycosides displayed notably greater potency than their 3R counterparts with differences of up to >1,000-fold between representative 3S and 3R pairings. Among the most active analogues, C3′-substitution presented a 3- to 5-fold enhancement in potency compared to C4′-functionalization. Among the pentose series amino and azido substitution was relatively interchangeable in the context of impact upon potency. In contrast, amino-substitution was found to be more advantageous in the context of the hexose series. The overall ranked order was Dg18 (3′-amino-D-xyloside, IC50 10 ± 1 nM) ≈ Dg17 (3′-azidoD-xyloside, IC50 17 ± 9 nM) ≥ Dg08 (4′-amino-D-glucoside, IC50 20 ± 6 nM) > Dg10 (3′-amino-D-glucoside, IC50 34 ± 4 nM) ≈ Dg15 (4′-azido-D-xyloside, IC50 34 ± 9 nM) ≈ Dg16 (4′-aminoD-xyloside, IC50 43 ± 8 nM) > Dg07 (4′-azido-D-glucoside, IC50 130 ± 25 nM) > Dg09 (3′-azido-D-glucoside, IC50 390 ± 18 nM). As is evident from the comparison of Dg08 (4′-amino-Dglucoside, IC50 20 ± 6 nM) and Dg12 (D-glucoside, IC50 1600 ± 400 nM), C4′-amino substitution presents the potential for dramatic improvement with a 80-fold difference. In an effort to better understand the corresponding SAR, neoglycoside-NKA docked models were developed based upon previously determined human NKA ligand-bound structures.54,55 Importantly, MD simulations of preferred binding modes track with experimentally determined inhibitor potency, suggesting this strategy to be potentially predictive for further inhibitor optimization. Notably, the side chains of four key NKA amino acids serve as the primary contributors to binding the sugar moiety in this model (E123, E319, D891, and K912) where a high degree of rotational freedom around the neoglycosidic bond leads to a divergence of predicted sugar orientations among the ligands compared. The conjugated pentose of the two most potent analogues Dg17 and Dg18 (Figure 4B,C, respectively) adopt an identical binding mode (with ligand sugar hydrogen bonding interactions contributed by the side chain carboxylate/amine of E123, D891, and K912) where the pentose C3′-azide/amine is notably fully solvent exposed. In contrast, a common feature of analogues with slightly lower potency (Dg08, Dg10, and Dg16; Figure 4D−F, respectively) is a key NKA E319 side chain carboxylate hydrogen bonding interaction with the corresponding sugar C3′ or C4′-amine, which effectively buries the carbohydrate amino group within the active site. Of these latter three analogues, a feature that further distinguishes the more potent Dg08 (Figure 4D) from the less active counterparts Dg10 and Dg16 (Figure 4E,F, respectively) is the presence of an additional Dg08 C2′-OH-NKA D891 side chain carboxylate hydrogen bonding interaction. Extrapolating from this computational model, a predicted buried sugar C2′-amine (by virtue of a hydrogen bond to the NKA D891-side chain carboxylate; Figure 4G) and additional sugar C6′-OH interaction with the NKA E319 side chain carboxylate may suggest C2′-aminosugar-derived analogues to display potencies similar to that of Dg08, Dg10, and Dg16. Cumulatively, this focused SAR study further extends a streamlined strategy for employing aminosugars within the context of neoglycosylation and reveals the C3-glycosylation of digitoxigenin with C3′-amino/azido-xylose to offer the most dramatic improvements in anticancer activity. Molecular modeling highlights a correlation of determined anticancer activity with favored NKA ligand-binding site occupancy where the corresponding C3′-amine/azide in the most active analogues were fully solvent exposed. This latter point also supports the contention that the C3 glycosylation of cardenolides (and potentially bufadenolides) with simple C3′-amino/azidosugars present convenient

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.5b00120. Corresponding experimental details and compound characterization data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Phone: 859-218-0141. E-mail: [email protected]. Funding

This work was supported by NIH R37 AI52218 (JST), the University of Kentucky College of Pharmacy, Markey Cancer Center, and the National Center for Advancing Translational Sciences (UL1TR000117). Notes

The authors declare the following competing financial interest(s): J.S.T. is a co-founder of Centrose (Madison, WI, USA).

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ACKNOWLEDGMENTS The authors thank Dr. Yinan Zhang for valuable discussion. ABBREVIATIONS CG, cardiac glycoside; ATPase, adenosine triphosphatase; NKA, Na+,K+-ATPase; NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; TGF-beta, transforming growth factor beta

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Influence of Sugar Amine Regiochemistry on Digitoxigenin

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